Primary control of the renin-angiotensin-aldosterone system occurs at the level of biosynthesis and secretion of renin. We propose an indepth biochemical and physiologic study of the various forms of plasma and tissue renins in order to elucidate mechanisms involved in control of renin biosynthesis. Our general hypothesis is 1) plasma and tissue inactive renin is prorenin, 2) several proteolytic steps may be involved in con-conversion of prorenin to active renin, and 3) clinical abnormalities in renin production may result from defects in conversion of prorenin to active renin. Specific aims include: 1) isolation and characterization of plasma and renal active and inactive renin, 2) a study of renin in normal and abnormal states of renin production in man, and 3) purification of human renal inactive renin from cadaver and fresh surgical kidney. Inactive renin is isolated and separated from active renin by affinity chromatography on cibracron-blue. Biochemical characterization includes kinetic activity, activation characteristics, molecular weight determination, binding to antihuman renin antibodies, isoelectric point determination, etc. Purification will include affinity chromatography on cibacron-blue, anti-renin antibody sepharose column, ion exchange chromatography, gel filtration, and possibly high pressure liquid chromatography. Plasma forms of renin will be studied in normals and patients following perturbations of the renin system. The proposal deals mainly with two clinical states: diabetes mellitus, in particular, diabetics with hyporeninemic hypoaldosteronism have marked increases in plasma inactive renin levels; and pregnancy, normal pregnant women also have marked increases in plasma inactive renin. Specific health related contributions include questions involving: 1) Could a block in conversion of inactive to active renin explain why diabetics have a high incidence of problems with blood pressure and potassium balance? Ultimately, could agents which convert inactive to active renin be used to normalize plasma renin activity and correct hyperkalemia? On the other hand, could agents which inhibit conversion be used in diagnosis of renin-dependent hypertensive states? Could increased levels of plasma inactive renin be an early indicator of diabetic renal disease? 2) Are changes in the forms of renin in pregnancy causally related or a reflection of alterations in volume? Could abnormal forms of renin be secreted by the uterus or placental membranes during preeclampsia which may be an indicator of placental ischemia?